Given the complexity of molecular networks involved in disease, the interruption of a single process often yields an insufficient therapeutic response. Although this fact is widely recognized, it is not clear how to overcome the problem. The prospect of targeting multiple pathways with a combination of small molecules (co-therapy) is complicated for the patient (and physician) by undesired side effect profiles and complicated dosing regimens and for the industry by a costly therapeutic discovery, development and approval path. The benefits of multi-target therapeutics are becoming particularly evident in cancer, with the recent approval of multi-receptor tyrosine kinase inhibitors such as sutent (PDGFR and VEGFR) and nexavar (BRAF and VEGFR) and with the plethora of pan-kinase inhibitors in clinical development (Zimmerman, 2007). This trend is not surprising, given that cancer cells possess the ability to utilize alternative signaling pathways for growth advantage and cell survival, a process that may even be facilitated by the use of selective targeted agents. Yet, the single compound, multi-targeting approach is laden with challenges; many targets require unique chemical matter for effective targeting, optimal potency at each target is elusive with one agent and nonselectivity is common. For all of the reasons stated above, novel strategies that target multiple pathways with highly specific inhibitors represent an attractive therapeutic alternative and provide a strong rationale for ongoing discovery efforts. At CytomX, instead of the so-called }dirty}, small molecule approach, we intend to demonstrate a new method for the discovery and assembly of site-specific multi-target peptide therapeutics. If successful, this first-generation integrated peptide therapeutic will be applicable to many targets and clinical problems. Within our laboratory resides unique expertise for the discovery of high affinity, high specificity peptides and kinetically-optimal peptide substrates for proteases. Each of these capabilities alone has been successful in the targeting of potential high value therapeutic targets. In this research, we will combine these technologies, both based on the iterative screening of bacterial display libraries, to develop and test the first site-directed, multi-targeted peptide therapeutic for cancer. A common goal in biological research is the discovery of better and safer medicines. Many approaches are being taken to solve this problem, ranging from specialized drug delivery nano-systems, to multi-targeted small molecules to direct targeting of the human genome. PUBLIC HEALTH RELEVANCE: we plan to apply our expertise in peptide discovery to address this world-wide issue and to develop a type of drug which is more active at the site of disease than it is in normal tissues and which targets more than one player in the disease process. Our goal is to make this approach general enough to be used for many different disease states but our research emphasis is currently in the field of angiogenesis. [unreadable] [unreadable] [unreadable]